How does keratin 17 control gene expression?
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Date
2014-06-30
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Johns Hopkins University
Abstract
The type I intermediate filament protein keratin 17 has been long implicated as a meaningful biomarker for a broad range of carcinomas (Moll et al., 1982), and there is emerging evidence that its expression impacts tumorigenesis and related processes. For instance, we recently showed that the genetic loss of K17 delays tumor onset in a mouse model of basal cell carcinoma, correlating with reduced tumor keratinocyte proliferation and a dramatic changes in the immune response in skin, from Th1/Th17- to a Th2-dominated cytokine profile (DePianto et al., 2010). There also is evidence that K17 impacts psoriasis, where again it would contribute to the dysregulation of the immune response (Fu and Wang, 2012). These and other studies suggest a link between K17, chronic hyperproliferative and inflammatory skin diseases, and the regulation of cytokine gene expression. The molecular mechanisms accounting for this intriguing link are not understood. A previously reported mass spectrometry-based screen (Chung et al., 2012) identified hnRNP K, an RNA/DNA-binding protein involved in many aspects of gene expression, as a K17 binding partner. Here we show that hnRNP K binds mRNA transcripts encoding the CXCR3 ligands CxCl9, CxCl10, and CxCl11, which are involved in pathogenesis of human basal cell carcinomas (Lo et al., 2010). Furthermore, induction of these genes is both K17- and hnRNP K-dependent, in both the A431 human skin cancer line and Gli2tg/+ mouse keratinocytes in primary culture. We also show that the expression of the CxCl9, CxCl10, and CxCl11 depends on RSK kinase activity. These findings identify a candidate mechanism through which hnRNP K and K17 exert a pro-tumorigenic influence, the robust stimulation of CXCR3 ligand expression.
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K17, hnRNP K, RSK, CXCR3, cancer, keratinocytes